Amyotrophic Lateral Sclerosis (ALS), also called Lou Gehrig's disease in the United States, is a late-onset, devastating fatal neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the spinal cord, motor cortex and brainstem. The goal of this U01 Blueprint grant is to optimize and develop small molecule activators of EAAT2 glutamate transporter protein expression as a means to treat ALS. EAAT2 expression is highly regulated at the translational level. In collaboration that was started more than 3 years ago with Dr. Lin at Ohio State University, we have identified molecules that increase expression of EAAT2 through a translational mechanism. Increased EAAT2 expression has been shown to compensate for the excessive excitotoxicity from high glutamate levels found in a number of diseases including ALS. The two lead molecules have been shown to cause a dose and time dependent increase in EAAT2 in a primary astrocyte cell line and in mouse spinal cord and brain. These compounds have been optimized to demonstrate proof-of-concept in vivo, but still need to be further optimized to improve potency and pharmacokinetic properties. Pharmacokinetic studies have been completed and acute and chronic maximum tolerated dose studies are in progress to help drive additional medicinal chemistry efforts.